Curcumin is regarded as a promising chemotherapeutic agent due to its anti-cancer activity and excellent biosafety. Nevertheless, the poor bioavailability and insufficient therapeutic efficacy have limited its further application in the clinic. Hence, we designed Janus magnetic mesoporous silica nanoparticles (Janus M-MSNs) for magnetically targeted and hyperthermia-enhanced curcumin treatment of liver cancer. In this study, curcumin was loaded into the silica components of Janus M-MSNs via surface-decorated pH-sensitive groups. Janus M-MSNs-Cur exhibited superior superparamagnetic properties, high curcumin loading ability and a tumor microenvironment-responsive curcumin release fashion. Additionally, an external magnetic field promoted the anti-tumor effectiveness of Janus M-MSNs-Cur through increasing the cellular internalization of Janus M-MSNs-Cur. More importantly, magnetic hyperthermia therapy supplemented the chemotherapeutic effect through a synergistic effect. Our outcomes demonstrated that Janus M-MSNs-Cur possessed a high therapeutic efficiency and excellent biosafety both in vitro and in vivo, indicating that Janus M-MSNs-Cur might be a promising therapeutic agent for liver cancer treatment.